Chronic Cytoprotection

FibroGen has an active research program to examine potential benefits of cytoprotective HIF-PHI in chronic degenerative diseases of the central nervous system, heart, and kidney, many of which have an underlying inflammatory component. For development purposes, FibroGen is focused on two neurodegenerative disease areas, multiple sclerosis and schizophrenia, in which exciting clinical data involving recombinant human EPO (rHuEPO) therapy has been reported.

EPO Benefits Demonstrated in Chronic Neurodegenerative Diseases

In a small study of chronic progressive multiple sclerosis patients treated with rHuEPO for 24 weeks, patients who received the high dose (48,000 IU rHuEPO), exhibited improvement of motor function and of cognitive performance, which persisted for 3-6 months after cessation of rhEPO therapy.1 Similarly, the results of a separate study of three month’s duration showed that patients with chronic schizophrenia who received a large dose (40,000 IU) of rHuEPO for 12 weeks had significant improvement over placebo patients in schizophrenia-related cognitive performance. The authors reported that rHuEPO is the first compound to exert a selective and lasting beneficial effect on cognition.2

Going Beyond EPO with HIF-PHI

In exploratory efforts using HIF-PHI, FibroGen and collaborators have generated impressive initial results in rodent models of multiple sclerosis and memory and learning, and in cellular models of Parkinson’s disease. A number of mechanistic studies conducted by FibroGen have begun to illuminate how HIF-PHI appear to provide therapeutic benefits beyond induction of EPO, including suppression of inflammatory cascades (discussed below), and bolstering the populations of endothelial progenitor cells (EPC) and hematopoietic progenitor cells in the bone marrow.3 EPC play a significant role in repairing ischemic tissue damage by promoting formation of new blood vessels at sites of damage.

Suppression of Inflammatory Pathways using HIF-PHI

Tissue hypoxia is implicated in both acute and chronic inflammatory diseases, and recent discoveries demonstrate a tissue-protective role of HIF in models of inflammation, which can be induced by treatment with HIF-PHI and is associated with suppression of inflammatory cytokines.

Tissue hypoxia and inflammation are especially apparent in conditions associated with damage to mucosal surfaces, such as those that line the colon. A monolayer of epithelial cells with specialized surfaces make up the mucosal barrier in the gut. This epithelial lining protects the body from antigens and pathogens present in the intestinal tract. It is a highly vascularized system, and, as such, it is susceptible to disruption of blood flow and subsequent hypoxia. Disruption of the gut barrier can lead to infection, inflammation, and fluid imbalance.

Using a murine model of colitic disease (chronic intestinal inflammation) it has been shown that HIF promotes an endogenous protective pathway in the gut at least in part through upregulation of genes that preserve the integrity of the mucosal barrier (e.g., ITF, CD73, MDR1, and GLUT-1).4-6 A more direct role for HIF expression in maintaining the integrity of the gut barrier has been demonstrated using transgenic mice with the HIF gene deleted from the intestinal epithelium. These mice experienced more severe clinical symptoms following experimentally induced colitis than wild-type control animals, whereas a second strain of transgenic mice that over-expressed HIF in the intestinal epithelium were protected.6 Chronic gastroinflammatory diseases, such as Crohn's disease and ulcerative colitis, are characterized by abnormalities of gut barrier function and increased HIF expression to compensate. 7,8

The ability of HIF-PHI to protect the gut barrier and reduce inflammation has recently been demonstrated in a murine mucosal inflammation model whereby administration of HIF-PHI resulted in HIF stabilization in the intestinal epithelium and symptom attenuation. Better outcomes in the HIF-PHI-treated group were associated with preservation of tissue architecture and suppression of inflammatory cytokines TNF-α and IFN-γ in vivo and promotion of tissue remodeling and wound healing in vitro. 9

Work at FibroGen indicates that HIF-PHI can also suppress other inflammatory cascades, reducing the production of inflammatory mediators, such as IL-6 and MCP-1,10 and inhibiting the differentiation of pro-inflammatory Type 1 Helper T Cells (TH1) cells from naive precursor T cells.11 Overactive TH1 cells are implicated in inflammatory and autoimmune diseases, such as multiple sclerosis and inflammatory bowel disease. The differentiation of TH1 cells from naive precursor cells (CD4+ TH0 cells) is dependent on the presence of the cytokine interleukin-12 (IL-12), making IL-12 a target for anti-inflammatory drug development . FibroGen’s in vitro data demonstrates that HIF-PHI can inhibit IL-12-induced TH1 differentiation by attenuating IL-12 signaling.

Given that inflammation is an important component of chronic neurodegenerative conditions, such as multiple sclerosis, and chronic inflammatory diseases, such as inflammatory bowel disease, there is the potential that cytoprotective efficacy of HIF-PHI in these settings will be enhanced by the ability to suppress the underlying inflammatory response.

References

  1. Ehrenreich et al. (2007) Exploring recombinant human erythropoietin in chronic progressive multiple sclerosis. Brain 130(Pt 10):2577-88.
  2. Ehrenreich et al. (2007) Improvement of cognitive functions in chronic schizophrenic patients by recombinant human erythropoietin. Mol Psychiatry 12(2):206-20.
  3. Sirenko et al. (2008) Proliferation and mobilization of endothelial progenitor cells in vivo stimulated by the novel HIF prolyl hydroxylase inhibitor FG-6513. Keystone Symposia Molecular, Cellular, Physiological and Pathogenic Responses of Hypoxia 2008: Abstract 413.
  4. Comerford, K.M., et al. (2002) Hypoxia-inducible factor-1-dependent regulation of the multidrug resistance (MDR1) gene. Cancer Res 62:3387–3394.
  5. Furuta, G.T., et al. (2001) Hypoxia-inducible factor 1-dependent induction of intestinal trefoil factor protects barrier function during hypoxia. J Exp Med 193:1027–1034.
  6. Karhausen J, et al. (2004) Epithelial hypoxia-inducible factor-1 is protective in murine experimental colitis. J Clin Invest Oct;114(8):1098-106.
  7. Lawrance IC, et al. (2001) Ulcerative colitis and Crohn's disease: distinctive gene expression profiles and novel susceptibility candidate genes. Hum Mol Genet 10:445–56.
  8. Giatromanolaki A, et al. (2003) Hypoxia inducible factor 1alpha and 2alpha overexpression in inflammatory bowel disease. J Clin Pathol 56:209–13.
  9. Robinson A, et al. (2008) Mucosal protection by hypoxia-inducible factor (HIF) prolyl hydroxylase inhibition. Gastroenterology 134(1):145-155.
  10. Wang, Q., et al. (2006) Renoprotective and therapeutic efficacy of the HIF prolyl hydroxylase inhibitor FG-4539 in experimental ischemia-reperfusion induced acute kidney injury JASN 17:325A.
  11. Chow, F. A., et al. (2008) HIF Prolyl Hydroxylase inhibitors attenuate IL-12-dependent inflammatory T Cell responses. Keystone Symposia Molecular, Cellular, Physiological and Pathogenic Responses of Hypoxia 2008: Abstract 140.
   

 
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